CN100420671C - Maleimide derivative and its preparation method and uses - Google Patents
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- CN100420671C CN100420671C CNB2004100583567A CN200410058356A CN100420671C CN 100420671 C CN100420671 C CN 100420671C CN B2004100583567 A CNB2004100583567 A CN B2004100583567A CN 200410058356 A CN200410058356 A CN 200410058356A CN 100420671 C CN100420671 C CN 100420671C
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Abstract
The present invention discloses a maleimide derivative, a preparing method thereof and the application thereof. The structural formula of the maleimide derivative of the present invention discloses in the general formula I, wherein R is an alkyl group containing 1 to 6 carbon atoms; R' is H or a methyl group; R' is H or a methyl group; X is NH or an S atom; M is an alkylidene group containing 2 to 18 carbon atoms; n is a positive integer between 3 and 4000. The method for preparing the maleimide derivative comprises; 1) under the action of a catalyst, bismaleimide is prepared from liphatic diamine and maleic anhydride, wherein the molar ratio of the aliphatic diamine to the maleic anhydride is 1 to (2.01 to 2.5); 2) PEG amine or PEG ethanethiol of which one end is methyl, ethyl, n-propyl or isopropyl reacts with the bismaleimide to obtain a product, wherein the molar ratio of the PEG amine or the PEG ethanethiol to the bismaleimide is 1 to (1.01 to 2.1). In the maleimide derivative of the present invention, the bismaleimide is used as a reaction raw material instead of the maleic anhydride, and the reaction product is single; when reacting with sulfhydryl and amino on protein, the maleimide derivative has specificity, and a dimer can not be generated. Thus, the maleimide derivative can be widely used in the field of protein modification.
Description
Technical field
The present invention relates to a kind of maleimide derivatives and preparation method thereof and application.
Background technology
The wetting ability polymer, as poly-alkyl diol, or other water-soluble, non-peptide class polymer etc., the covalent bonding technology with molecule or surface is widely used in biotechnology and field of medicaments.Polyoxyethylene glycol (PEG) is a kind of poly-alkyl diol commonly used, and it is the linear polymer that two ends are hydroxyl, and its structure can be expressed as:
Wherein, n is the integer between the 3-4000.
Also following formula can be expressed as HO-PEG-OH
Then wherein PEG represents,
Normally used PEG is H
3C-O-PEG-OH, promptly poly glycol monomethyl ether is represented with mPEG.Wherein, main chain one end is a mono methoxy; The main chain the other end is a hydroxyl, and this hydroxyl can be converted into other functional groups, or connects upward other functional groups, is used for chemically modified.The structure of mPEG can be expressed as following formula:
Wherein, n is the integer between the 3-4000.
The chemical property of polyoxyethylene and polyoxypropylene and PEG is close, can replace PEG in a lot of Application Areass.Its molecular formula general formula is expressed as follows:
Wherein, n is the integer between the 3-4000; R represents hydrogen atom or methyl.
PEG is soluble in water, has thermostability and biocompatibility, and its aqueous solution is colourless, tasteless clear solution, also dissolves in the number of chemical solvent, and not hydrolysis is not degraded, and is normally nontoxic.In addition, the PEG non-immunogenicity can not induce body to produce immune response.When PEG with after the molecule that contains corresponding reactive site is connected, PEG can reduce even eliminate the immune response of institute's link molecule, makes organism ignore the existence of this molecule, allows it to be present in the organism.The another kind effect of PEG is the solubleness that increases " insoluble molecule-PEG " binding substances, and for example, paclitaxel is water insoluble, in conjunction with the conjugates of PEG water soluble (Greenwald, et al., J.org.chem., 60,331-336,1995) then.
Be used for protein modified PEG molecule, the PEG end need be converted into active function groups usually, this functional group can select according to the active group on target protein or the peptide molecule.For example, free sulfydryl on the corresponding protein molecular can select for use the PEG of maleimide, iodoacetic acid ester, vinyl sulfonic acid ester derivatize to carry out coupled reaction.
The patent of Shearwater.co company (US:6602498) described maleimide polymer derivative with and the preparation method of derivative, the polymer and the maleic anhydride that promptly contain amido functional group, under sodium-acetate and aceticanhydride effect, be prepared from through two-step reaction.And need the separation and purification operation between the two-step reaction, in order to remove intermediate product toxilic acid monoamide.The product dimaleoyl imino monomethoxypolyethylglycol glycol derivative purity of this method and reduces with the increase of polymer molecule of the skeleton amount between 79%～90%.Exist complicated ion exchange chromatography and precipitation technology etc. in this production technique and separate purification process.
Summary of the invention
The purpose of this invention is to provide simple succinimide derivative of a kind of preparation and preparation method thereof.
Maleimide derivatives provided by the present invention has the structural formula of general formula I, and wherein, R is the alkyl of 1-6 carbon atom; R ' is H or methyl; R " be H or methyl; X is NH or S atom; M is the alkylidene group of 2-18 carbon atom; N is the positive integer between the 3-4000.
Described R comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, 2-methyl-propyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl, isohexyl and alkyl isomers thereof; Be preferably methyl, ethyl, n-propyl or sec.-propyl; Methyl more preferably.
Described R ' is preferably H; Described R " be preferably H.Described n is preferably the positive integer between the 113-1500.Described X is preferably NH.
Described M represents carbonatoms alkylidene group between 2-18, can be the alkylidene group of side chain or linear chain structure, comprises ethylidene, propylidene, isopropylidene, butylidene, 2-methyl propylidene, pentylidene, hexylidene etc.; Be preferably the straight-chain alkyl-sub-of C2-C6, wherein more commonly used is ethylidene.
The preparation method of this succinimide derivative, comprise the steps: 1) preparation bismaleimide sulfonamide derivatives: with mol ratio is 1: the aliphatie diamine of 2.01-2.5 and maleic anhydride are at acetone or dimethyl sulfoxide (DMSO) or N, react in the dinethylformamide, add aceticanhydride and catalyzer then, reaction obtains the bismaleimide sulfonamide derivatives; Described catalyzer is selected from one or more the combination in sodium acetate, potassium acetate, amine acetate and the magnesium acetate;
2) be 1 with mol ratio: the end of 1.01-2.1 is that the PEG amine of methyl, ethyl, n-propyl or sec.-propyl or PEG sulfur alcohol and bismaleimides are heated to 40 ℃-80 ℃ in chloroform or methylene dichloride or acetone, and reaction obtains product.
In aforesaid method, the described catalyst levels of step 1) is that per 5 gram maleic anhydrides add catalyzer 0.1-0.5g, and its reaction is to carry out 2-10h under 25 ℃ of-100 ℃ of conditions, wherein preferably carries out 4-6h under 50 ℃ of-80 ℃ of conditions; Step 2) the preferred temperature of described reaction is 65 ℃-80 ℃, and the reaction times is 1.5-3.5 hour.
Wherein, step 2) used reaction raw materials one end is that the PEG amine of methyl, ethyl, n-propyl or sec.-propyl or PEG sulfur alcohol can be bought and obtain, also can be synthetic when preparation derivative of the present invention.
Succinimide derivative of the present invention can with functional group covalent attachment such as sulfydryl, amino, particularly covalently bound active high with free sulfhydryl groups, be suitable for modifying the albumen or the peptide molecule that contain one or more cysteine sulfydryls.
The reaction formula for preparing succinimide derivative of the present invention is as follows:
Annotate .X and represent NH or S
Succinimide derivative characteristics provided by the present invention are, replace maleic anhydride to participate in reaction as reaction raw materials with bismaleimides, and the gained reaction product is single; Have specificity with sulfydryl on the albumen, amino reaction, and modification can not produce crosslinked by product, generate dimer, can in modifying protein and polypeptide, be used widely.
Description of drawings
Fig. 1 is the ultra-violet absorption spectrum of mPEG-NS-MAL;
Fig. 2 is the SDS-PAGE electrophorogram of mPEG-NS-BSA;
Fig. 3 is the SDS-PAGE electrophorogram of mPEG-NS-rINF-γ.
Embodiment
1, preparation N-maleimide ethyl maleimide
In the 250ml three-necked bottle, add 5g maleic anhydride (0.051mol), acetone 20ml (density: 0.789g/ml), be stirred to molten entirely.Quadrol 1.65ml is dissolved in 12ml acetone, splashes in the maleic anhydride acetone soln, stirring at room reaction 3h.Add triethylamine 2ml (0.0143mol) then, stirring at room reaction 30min.Add anhydrous sodium acetate 0.1g, slowly drip the 10ml aceticanhydride, 65 ℃ are stirred 4h.Reaction finishes, and filters concentrating under reduced pressure.Use the 100ml acetone solution, after shaking up, with under the solution stirring to going in the 500ml anhydrous diethyl ether, separate out the brown precipitation.Filtration under diminished pressure is collected crystal.40 ℃ of drying under reduced pressure obtain N-maleimide ethyl maleimide.
2, preparation mPEG
5k-NH
2
10g (2mmol) mPEG-5000 is dissolved in 400ml CHCl
3, 90 ℃ of air distillations boil off 200ml CHCl
3, be cooled to room temperature.Nitrogen protection adds 0.72ml triethylamine and 0.4ml methylsulfonyl chloride, stirred overnight at room temperature down.Add 2ml ethanol termination reaction then, concentrate solvent evaporated behind the stirring 15min, use ether sedimentation.Add 250ml strong aqua and 5g NH
4Cl, stirring at room reaction 72h uses dichloromethane extraction then, and anhydrous sodium sulfate drying concentrates, and ether sedimentation promptly gets pure product.
3, preparation mPEG
5k-N-substituted succinimide ethylidene maleimide
0.42gN-the maleimide ethyl maleimide joins in the 100ml chloroform, adds 5g mPEG
5k-NH
2, be heated to 65 ℃ of stirring reaction 2.5h.Stirred overnight at room temperature then, after reaction finishes after filtration, concentrate and ether sedimentation.Precipitation is filtered with the dissolving of 100ml tetrachloromethane, concentrates, and 100ml Virahol recrystallization obtains mPEG
5k-N-substituted succinimide ethylidene maleimide.
The product fusing point is 60 ℃, and color is white, and is slightly light yellow.The product UV spectrum proves that product is correct as shown in Figure 1.
NMR：δH(CDCl
3)6.72(2H，S，CH＝CH)，δ3.5(br?m，PEG)，δ3.38(3H，S，-OCH
3)。
1, preparation N-maleimide hexyl maleimide
The preparation method is with embodiment 1 preparation N-maleimide ethyl maleimide, so difference is being reacted 0.024mol hexanediamine and 5g maleic anhydride in DMF, catalyst system therefor is the 0.25g ammonium acetate, is reflected to carry out 10h under 25 ℃.Steps such as the precipitation after reaction finishes, crystallization are identical with embodiment 1, obtain N-maleimide hexyl maleimide.
2, preparation mPEG
5k-N-substituted succinimide hexylidene maleimide
The preparation method is with embodiment 1 preparation mPEG
5k-N-substituted succinimide ethylidene maleimide is so difference is with 0.279gN-maleimide hexyl maleimide and 5gmPEG
5k-NH
2In acetone, react 3h at 40 ℃.Steps such as the precipitation after reaction finishes, crystallization are identical with embodiment 1, obtain mPEG
5k-N-substituted succinimide hexylidene maleimide.
The product fusing point is 60 ℃, and color is white, and is slightly light yellow.
NMR：δH(CDCl
3)6.72(2H，S，CH＝CH)，δ3.5(br?m，PEG)，δ3.38(3H，S，-OCH
3)。
1, preparation mPEG
10k-NH
2
The preparation method is with embodiment 1 preparation mPEG
5k-NH
2, difference is that reaction raw materials is mPEG-10000.
2, preparation mPEG
10k-N-substituted succinimide ethylidene maleimide
The preparation method is with embodiment 1 preparation mPEG
5k-N-substituted succinimide ethylidene maleimide is so difference is with 0.231gN-maleimide ethyl maleimide and 5gmPEG
10k-NH
2In methylene dichloride, react 3.5h at 80 ℃.Steps such as the precipitation after reaction finishes, crystallization are identical with embodiment 1, obtain mPEG
10k-N-substituted succinimide ethylidene maleimide.
The product fusing point is 60 ℃, and color is white, and is slightly light yellow.
NMR：δH(CDCl
3)6.72(2H，S，CH＝CH)，δ3.5(br?m，PEG)，δ3.38(3H，S，-OCH
3)
1, preparation N-maleimide butyl maleimide
The preparation method is with embodiment 1 preparation N-maleimide ethyl maleimide, so difference is being reacted 1.796g butanediamine and 5g maleic anhydride in DMSO, catalyst system therefor is the 0.5g magnesium acetate, is reflected to carry out 2h under 100 ℃.Steps such as the precipitation after reaction finishes, crystallization are identical with embodiment 1, obtain N-maleimide butyl maleimide.
2, preparation mPEG
20k-NH
2
The preparation method is with embodiment 1 preparation mPEG
5k-NH
2, difference is that reaction raw materials is mPEG-20000.
3, preparation mPEG
20k-N-substituted succinimide butylidene maleimide
The preparation method is with embodiment 1 preparation mPEG
5k-N-substituted succinimide ethylidene maleimide is so difference is with 0.13gN-maleimide butyl maleimide and 5gmPEG
20k-NH
2In acetone, react 3.5h at 65 ℃.Steps such as the precipitation after reaction finishes, crystallization are identical with embodiment 1, obtain mPEG
20k-N-substituted succinimide butylidene maleimide.
The product fusing point is 62 ℃, and color is white, and is slightly light yellow.
NMR：δH(CDCl
3)6.72(2H，S，CH＝CH)，δ3.5(br?m，PEG)，δ3.38(3H，S，-OCH
3)
1, preparation mPEG
40k-NH
2
The preparation method is with embodiment 1 preparation mPEG
5k-NH
2, difference is that reaction raw materials is mPEG-40000.
2, mPEG
40k-N-substituted succinimide ethylidene maleimide
The preparation method is with embodiment 1 preparation mPEG
5k-N-substituted succinimide ethylidene maleimide is so difference is with 0.041gN-maleimide ethyl maleimide and 5gmPEG
40k-NH
2In methylene dichloride, react 3.5h at 70 ℃.Steps such as the precipitation after reaction finishes, crystallization are identical with embodiment 1, obtain mPEG
40k-N-substituted succinimide ethylidene maleimide.
The product fusing point is 61 ℃, and color is white, and is slightly light yellow.
NMR：δH(CDCl
3)6.72(2H，S，CH＝CH)，δ3.5(br?m，PEG)，δ3.38(3H，S，-OCH
3)
Embodiment 6, mPEG
10k(R is a methyl among the formula I in the preparation of-N-substituted succinimide hexylidene maleimide; R ' is H; R " be H; X is NH; M is a hexylidene; N is 227)
The preparation method is with embodiment 1 preparation mPEG
5k-N-substituted succinimide ethylidene maleimide is so difference is with 0.248gN-maleimide hexyl maleimide and 5gmPEG
10k-NH
2In methylene dichloride, react 3.5h at 70 ℃.Steps such as the precipitation after reaction finishes, crystallization are identical with embodiment 1, obtain mPEG
10k-N-substituted succinimide hexylidene maleimide.
The product fusing point is 61 ℃, and color is white, and is slightly light yellow.
NMR：δH(CDCl
3)6.72(2H，S，CH＝CH)，δ3.5(br?m，PEG)，δ3.38(3H，S，-OCH
3)
Embodiment 7, mPEG
20k(R is a methyl among the formula I in the preparation of-N-substituted succinimide ethylidene maleimide; R ' is H; R " be H; X is NH; M is an ethylidene; N is 454)
The preparation method is with embodiment 1 preparation mPEG
5k-N-substituted succinimide ethylidene maleimide is so difference is with 0082gN-maleimide ethyl maleimide and 5gmPEG
20k-NH
2In methylene dichloride, react 3.5h at 75 ℃.Steps such as the precipitation after reaction finishes, crystallization are identical with embodiment 1, obtain mPEG
20k-N-substituted succinimide ethylidene maleimide.
The product fusing point is 61 ℃, and color is white, and is slightly light yellow.
NMR：δH(CDCl
3)6.72(2H，S，CH＝CH)，δ3.5(br?m，PEG)，δ3.38(3H，S，-OCH
3)
Embodiment 8, mPEG
20k(R is a methyl among the formula I in the preparation of-N-substituted succinimide hexylidene maleimide; R ' is H; R " be H; X is NH; M is a hexylidene; N is 454)
The preparation method is with embodiment 1 preparation mPEG
5k-N-substituted succinimide ethylidene maleimide is so difference is with 0.097gN-maleimide hexyl maleimide and 5gmPEG
20k-NH
2In methylene dichloride, react 3h at 75 ℃.Steps such as the precipitation after reaction finishes, crystallization are identical with embodiment 1, obtain mPEG
20k-N-substituted succinimide hexylidene maleimide.
The product fusing point is 62 ℃, and color is white, and is slightly light yellow.
NMR：δH(CDCl
3)6.72(2H，S，CH＝CH)，δ3.5(br?m，PEG)，δ3.38(3H，S，-OCH
3)。
Embodiment 9, mPEG
5k(R is a methyl among the formula I in the preparation of-N-substituted succinimide propylidene maleimide; R ' is H; R " be H; X is NH; M is a propylidene; N is 113)
1, preparation N-maleimide propyl group maleimide
The preparation method is with embodiment 1 preparation N-maleimide ethyl maleimide, so difference is being reacted 1.573g propylene diamine and 5g maleic anhydride in DMF, catalyst system therefor is the 0.4g potassium acetate, is reflected to carry out 6h under 50 ℃.Steps such as the precipitation after reaction finishes, crystallization are identical with embodiment 1, obtain N-maleimide propyl group maleimide.
2, preparation mPEG
5k-N-substituted succinimide propylidene maleimide
The preparation method is with embodiment 1 preparation mPEG
5k-N-substituted succinimide ethylidene maleimide is so difference is with 0.243gN-maleimide propyl group maleimide and 5gmPEG
5k-NH
2In methylene dichloride, react 2h at 75 ℃.Steps such as the precipitation after reaction finishes, crystallization are identical with embodiment 1, obtain mPEG
5k-N-substituted succinimide propylidene maleimide.
The product fusing point is 60 ℃, and color is white, and is slightly light yellow.
NMR：δH(CDCl
3)6.72(2H，S，CH＝CH)，δ3.5(br?m，PEG)，δ3.38(3H，S，-OCH
3)。
Embodiment 10, mPEG
20k(R is a methyl among the formula I in the preparation of-N-substituted succinimide pentylidene maleimide; R ' is H; R " be H; X is NH; M is a pentylidene; N is 454)
1, preparation N-maleimide amyl group maleimide
The preparation method is with embodiment 1 preparation N-maleimide ethyl maleimide, so difference is being reacted 2.59g pentamethylene diamine and 5g maleic anhydride in DMSO, catalyst system therefor is 0.2g potassium acetate and 0.1g ammonium acetate, is reflected to carry out 4h under 80 ℃.Steps such as the precipitation after reaction finishes, crystallization are identical with embodiment 1, obtain N-maleimide amyl group maleimide.
2, preparation mPEG
20k-N-substituted succinimide pentylidene maleimide
The preparation method is with embodiment 1 preparation mPEG
5k-N-substituted succinimide ethylidene maleimide is so difference is with 0.138gN-maleimide amyl group maleimide and 5gmPEG
20k-NH
2In acetone, react 3.5h at 75 ℃.Steps such as the precipitation after reaction finishes, crystallization are identical with embodiment 1, obtain mPEG
20k-N-substituted succinimide pentylidene maleimide.
The product fusing point is 61 ℃, and color is white, and is slightly light yellow.
NMR：δH(CDCl
3)6.72(2H，S，CH＝CH)，δ3.5(br?m，PEG)，δ3.38(3H，S，-OCH
3)。
Embodiment 11, preparation mPEG
5k(R is a methyl to-S-(N-substituted succinimide ethylidene) maleimide among the formula I; R ' is H; R " be H; X is S; M is an ethylidene; N is 113)
Method by embodiment 1 prepares N-maleimide ethyl maleimide, gets 0.42gN-maleimide ethyl maleimide and joins in the 100ml chloroform, adds 5g mPEG
5k-SH (purchasing company) in Nektar Therapeutics, stirring at room reaction 2.5h.After reaction finishes after filtration, concentrate and ether sedimentation.Precipitation is filtered with the dissolving of 100ml tetrachloromethane, concentrates, and 100ml Virahol recrystallization obtains mPEG
5k-S-(N-substituted succinimide ethylidene) maleimide.
The product fusing point is 60 ℃, and color is white, and is slightly light yellow.The product UV spectrum proves that product is correct as shown in Figure 1.
NMR：δH(CDCl
3)6.72(2H，S，CH＝CH)，δ3.5(br?m，PEG)，δ3.38(3H，S，-OCH
3)。
The PEG sulfur alcohol that other ends are ethyl, n-propyl or sec.-propyl also can be bought from Nektar Therapeutics company and obtain, and adopts above-mentioned preparation method can obtain that R is maleimide derivatives such as ethyl, n-propyl or sec.-propyl among the formula I.
Embodiment 12, mPEG
5kThe amine-modified bovine serum albumin of-N-substituted succinimide hexylidene maleimide (BSA)
Bovine serum albumin (BSA) is after DTT (DTT) is handled, with mPEG
5k-N-substituted succinimide hexylidene maleimide (making by embodiment 2 methods) is to react under the pH6.0 condition in 1: 1 and 1: 5 with mol ratio respectively, obtains low the modification and high modified outcome respectively.Modifying method adopts conventional maleimide derivatives modifying method, and the SDS-PAGE electrophoretogram of product as shown in Figure 2.The M road is a standard molecular weight albumen among the figure; 1 road is the BSA reference substance; 2 roads are the low mPEG-NS-BSA biased sample of modifying; 3 roads are the low mPEG-NS-BSA biased sample of modifying; 4 roads are the high mPEG-NS-BSA of modification biased sample, wherein-NS-represents N substituted succinimide base ,-BSA represents bovine serum albumin.Electrophoresis result shows that BSA has one or more and modifies band.
Embodiment 13, mPEG
5kThe amine-modified rINF-γ of-N-substituted succinimide ethylidene maleimide
Buy recombinant protein 97Cys-rINF-γ and 131Cys-rINF-γ (the 97th of the N-terminal of INF-γ or 131 amino acids residues sport halfcystine) from SCHERING CORPORATION company, the mPEG that makes with embodiment 1
5k-N-substituted succinimide ethylidene maleimide is modified above-mentioned two kinds of albumen.
Adding 3ml concentration in the 50mmol sodium-acetate buffer is the 97Cys-rINF-γ of 0.36mg/ml, regulates pH3.6, adds mPEG
5k-N-substituted succinimide ethylidene maleimide 6mg, room temperature reaction 2 hours can get the modified outcome mPEG-NS-97Cys-rINF-γ of 50%～80% yield.
MPEG-NS-131Cys-rINF-γ preparation method is with last identical.
When preparation mPEG-NS-97Cys-rINF-γ, room temperature reaction adds 30 mmole DTT in reaction system after 2 hours, obtain mPEG-NS-97Cys-rINF-γ and modify sample, contains DTT (DTT) 30 mmoles.
The SDS-PAGE electrophorogram of several products as shown in Figure 3, the M road is a standard molecular weight albumen among the figure; 1 road is a 97Cys-rINF-γ inclusion body; Sample is modified for mPEG-NS-97Cys-rINF-γ in 2 roads; 3 roads are 131Cys-rINF-γ inclusion body; Sample is modified for mPEG-NS-131Cys-rINF-γ in 4 roads; Sample is modified for the mPEG-NS-97Cys-rINF-γ that contains DTT (DTT) 30 mmoles in 5 roads.Electrophoresis result shows mPEG
5k-N-substituted succinimide ethylidene maleimide has good modification effect to rINF-γ.
Claims (10)
1. structural formula is the maleimide derivatives of general formula I, and wherein, R is the alkyl of 1-6 carbon atom; R ' is H or methyl; R " be H or methyl; X is NH or S atom; M is the alkylidene group of 2-18 carbon atom; N is the positive integer between the 3-4000;
2. derivative according to claim 1 is characterized in that: described R is methyl, ethyl, n-propyl or sec.-propyl.
3. derivative according to claim 2 is characterized in that: described R is a methyl; Described R ' is H; Described R " be H.
4. according to claim 1 or 2 or 3 described derivatives, it is characterized in that: described n is the positive integer between the 113-1500.
5. according to claim 1 or 2 or 3 described derivatives, it is characterized in that: described X is NH; Described M is the straight-chain alkyl-sub-of 2-6 carbon atom.
6. derivative according to claim 5 is characterized in that: described M is an ethylidene.
7. the preparation method of the described derivative of claim 2, comprise the steps: 1) preparation bismaleimide sulfonamide derivatives: with mol ratio is 1: the aliphatie diamine of 2.01-2.5 and maleic anhydride are at acetone or dimethyl sulfoxide (DMSO) or N, react in the dinethylformamide, add aceticanhydride and catalyzer then, reaction obtains the bismaleimide sulfonamide derivatives; Described catalyzer is selected from one or more the combination in sodium acetate, potassium acetate, amine acetate and the magnesium acetate;
2) be 1 with mol ratio: the end of 1.01-2.1 is that the PEG amine of methyl, ethyl, n-propyl or sec.-propyl or PEG sulfur alcohol and bismaleimide sulfonamide derivatives are heated to 40 ℃-80 ℃ in chloroform or methylene dichloride or acetone, and reaction obtains product.
8. preparation method according to claim 7 is characterized in that: the described catalyst levels of step 1) is that per 5 gram maleic anhydrides add catalyzer 0.1-0.5g, and its reaction is to carry out 2-10h under 25 ℃ of-100 ℃ of conditions; Step 2) described temperature of reaction is 65 ℃-80 ℃, and the reaction times is 1.5-3.5 hour.
9. preparation method according to claim 8 is characterized in that: the described reaction of step 1) is to carry out 4-6h under 50 ℃ of-80 ℃ of conditions.
10. the application of the described derivative of claim 1-6 in modifying protein or polypeptide.
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| CN107045064A (en) * | 2017-01-13 | 2017-08-15 | 中国药科大学 | A kind of pre-treating method of polypeptide based on derivatization in plasma sample |
| CN108129659B (en) * | 2017-12-25 | 2020-11-10 | 山东圣泉新材料股份有限公司 | Bismaleimide composition and preparation method thereof |
| CN111253572B (en) * | 2018-04-13 | 2022-06-03 | 苏州大学 | Preparation method of bismaleimide-based thermosetting shape memory resin |
| CN110437122A (en) * | 2019-08-06 | 2019-11-12 | 山东阳谷华泰化工股份有限公司 | A kind of rubber anti-recovery agent 1,3- bismaleimide n-propane and its synthetic method |
| CN113024774A (en) * | 2021-03-18 | 2021-06-25 | 三棵树(上海)新材料研究有限公司 | Epoxy curing agent containing maleimide structure and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6602498B2 (en) * | 2000-02-22 | 2003-08-05 | Shearwater Corporation | N-maleimidyl polymer derivatives |
| CN1511860A (en) * | 2002-12-26 | 2004-07-14 | 北京键凯科技有限公司 | Poly glycol long chain fatty alkyl maleimide derivative and its medicinal combination |
| CN1511861A (en) * | 2002-12-26 | 2004-07-14 | 北京键凯科技有限公司 | Polyglycol fatty acid derivative and its medicinal combination |
-
2004
- 2004-08-12 CN CNB2004100583567A patent/CN100420671C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6602498B2 (en) * | 2000-02-22 | 2003-08-05 | Shearwater Corporation | N-maleimidyl polymer derivatives |
| CN1511860A (en) * | 2002-12-26 | 2004-07-14 | 北京键凯科技有限公司 | Poly glycol long chain fatty alkyl maleimide derivative and its medicinal combination |
| CN1511861A (en) * | 2002-12-26 | 2004-07-14 | 北京键凯科技有限公司 | Polyglycol fatty acid derivative and its medicinal combination |
Non-Patent Citations (2)
| Title |
|---|
| 合成条件对双马来酰亚胺合成的影响. 刘润山.化学试剂，第7卷第6期. 1985 |
| 合成条件对双马来酰亚胺合成的影响. 刘润山.化学试剂，第7卷第6期. 1985 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1733721A (en) | 2006-02-15 |
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